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1.
Artigo em Inglês | MEDLINE | ID: mdl-33067779

RESUMO

PURPOSE: Many studies have revealed that statin therapy reduced mortality in cancer patients, especially in breast cancer, but the effect for second cancer was unclear. We, therefore, performed a comparable cohort study to determine the risk of second cancer in breast cancer patients with statin therapy. METHODS: Using claims data from Taiwan's National Health Insurance Program, this study enrolled newly diagnosed breast cancer patients from 2000 to 2007 with and without statin therapy as the statin (n = 1222) and nonstatin (n = 4888) cohorts, respectively. The nonstatin cohort was propensity score matched by cohort entry year, age, and randomly selected comorbidities. These two cohorts were followed up until the diagnosis of second cancer, death, or the end of 2011. Cox proportional hazard models were used to estimate the hazard ratios. RESULTS: The statin cohort had a lower incidence rate than the nonstatin cohort for second cancer (7.37 vs. 8.36 per 1000 person-years), although the difference was not significant (adjusted hazard ratio [aHR] 0.90, 95% confidence interval [CI] 0.65-1.26). Compared with the nonstatin cohort, the second cancer risk was significantly higher for patients taking pravastatin (aHR 2.71, 95% CI 1.19-6.19) but lower for those receiving multiple statin treatment (aHR 0.45, 95% CI 0.25-0.81) and combined lipophilic and hydrophilic type of statin (aHR 0.42, 95% CI 0.20-0.89). The risk was lower for patients receiving a cumulative defined daily dose (cDDD) of > 430 (aHR 0.41, 95% CI 0.19-0.86). CONCLUSION: This study showed that there is little association between statin use and second cancer risk in breast cancer patients.

2.
Retrovirology ; 17(1): 34, 2020 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-33008414

RESUMO

BACKGROUND: Koalas are infected with the koala retrovirus (KoRV) that exists as exogenous or endogenous viruses. KoRV is genetically diverse with co-infection with up to ten envelope subtypes (A-J) possible; KoRV-A is the prototype endogenous form. KoRV-B, first found in a small number of koalas with an increased leukemia prevalence at one US zoo, has been associated with other cancers and increased chlamydial disease. To better understand the molecular epidemiology of KoRV variants and the effect of increased viral loads (VLs) on transmissibility and pathogenicity we developed subtype-specific quantitative PCR (qPCR) assays and tested blood and tissue samples from koalas at US zoos (n = 78), two Australian zoos (n = 27) and wild-caught (n = 21) in Australia. We analyzed PCR results with available clinical, demographic, and pedigree data. RESULTS: All koalas were KoRV-A-infected. A small number of koalas (10.3%) at one US zoo were also infected with non-A subtypes, while a higher non-A subtype prevalence (59.3%) was found in koalas at Australian zoos. Wild koalas from one location were only infected with KoRV-A. We observed a significant association of infection and plasma VLs of non-A subtypes in koalas that died of leukemia/lymphoma and other neoplasias and report cancer diagnoses in KoRV-A-positive animals. Infection and VLs of non-A subtypes was not associated with age or sex. Transmission of non-A subtypes occurred from dam-to-offspring and likely following adult-to-adult contact, but associations with contact type were not evaluated. Brief antiretroviral treatment of one leukemic koala infected with high plasma levels of KoRV-A, -B, and -F did not affect VL or disease progression. CONCLUSIONS: Our results show a significant association of non-A KoRV infection and plasma VLs with leukemia and other cancers. Although we confirm dam-to-offspring transmission of these variants, we also show other routes are possible. Our validated qPCR assays will be useful to further understand KoRV epidemiology and its zoonotic transmission potential for humans exposed to koalas because KoRV can infect human cells.

3.
Artigo em Inglês | MEDLINE | ID: mdl-33104503

RESUMO

The accurate prediction of glioma grade is essential for treatment planning and prognosis. In this study, we proposed a novel radiomics-based pipeline by incorporating the intratumoral and peritumoral features extracted from preoperative mpMRI scans to accurately and noninvasively predict glioma grade. To address the unclear peritumoral boundary, we designed an algorithm to capture the peritumoral region with a specified radius. The mpMRI scans of 285 patients derived from a multi-institutional study were adopted. A total of 2153 radiomic features were calculated separately from intratumoral volumes (ITVs) and peritumoral volumes (PTVs) on mpMRI scans, and then refined using LASSO and mRMR feature ranking methods. The top-ranking radiomic features were entered into the classifiers to build radiomic signatures for predicting glioma grade. The prediction performance was evaluated with five-fold cross-validation on a patient-level split. The radiomic signatures utilizing the features of ITV and PTV both show a high accuracy in predicting glioma grade, with AUCs reaching 0.968. By incorporating the features of ITV and PTV, the AUC of IPTV radiomic signature can be increased to 0.975, which outperforms the state-of-the-art methods. Additionally, our proposed method was further demonstrated to have strong generalization performance in an external validation dataset with 65 patients.

4.
J Affect Disord ; 278: 12500, 2020 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-33035948

RESUMO

BACKGROUND: To clarify the longitudinal risk factors for mortality in older people with bipolar disorder (BD) and major depressive disorder (MDD). METHODS: This study is a national cohort study of older patients with mood disorders. Patients were identified from Taiwan's National Health Insurance Research Database and followed from 2008 to 2011. We determined the mortality rates and standardized mortality ratios (SMRs) in this study population. Survival analyses were conducted to examine factors and healthcare utilization patterns associated with mortality during the 3-year follow-up period. RESULTS: 26,570 patients aged ≥ 65 years and diagnosed with and treated for BD or MDD in 2008 were enrolled (5,854 and 20,716 with BD and MDD, respectively). Within the 3-year follow-up period, 15.24% (n=4048) of the enrolled patients died, including 1003 (17.13%) in the BD and 3045 (14.70%) in the MDD groups. The SMRs for BD and MDD were 1.65 (1.56-1.76), and 1.26 (1.21-1.32), respectively. Among the examined comorbidities, dementia, diabetes mellitus and renal diseases each constituted an elevated relative mortality risk. By contrast, hypertension and hyperlipidemia were associated with a lower risk of mortality. LIMITATION: In Taiwan's National Health Insurance program, specific medications are prescribed for specific diagnoses and confounding by indication should be kept in mind. CONCLUSION: Older patients with mood disorders had a relatively high mortality risk over the 3-year follow-up period. Early detection, risk prevention, and better management of comorbid physical and mental disorders can improve the health outcomes of older patients with BD and MDD.

5.
Emerg Microbes Infect ; 9(1): 2094-2104, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32912064

RESUMO

Acinetobacter baumannii emerged as one of the most important pathogens that causes nosocomial infections due to its increased multidrug resistance. Identifying capsular epidemiology in A. baumannii can aid in the development of effective treatments and preventive measures against this emerging pathogen. Here we established a wzc-based method, and combined it with wzy-PCR to determine capsular types of A. baumannii causing nosocomial bacteraemia collected at two medical centres in Taiwan from 2015 to 2017. Among the 237 patients with A. baumannii bacteraemia, 98 (41.4%) isolates were resistant to carbapenems. Four prevalent capsular types (KL2, KL10, KL22, and KL52) accounted for 84.7% of carbapenem-resistant A. baumannii (CRAB) and 12.2% of non-CRAB. The rate of pneumonia, intensive care unit admission, APACHE II score, and Pitt bacteraemia score were higher in patients with KL2/10/22/52 infection than in those with non-KL2/10/22/52 infection. Patients with KL2/10/22/52 infection and patients with CRAB infection have a higher cumulative incidence of attributable and all-cause in-hospital 30-day mortality. On multivariate analysis, appropriate empirical antimicrobial therapy within 24 h was associated with a lower risk of 30-day attributable mortality in the KL2/10/22/52 isolates (odds ratio = 0.19, 95% CI: 0.06-0.66, p = 0.008) but not in non-KL2/10/22/52 isolates. Early recognition of carbapenem resistance-associated capsular types may help clinicians to promptly implement appropriate antimicrobial therapy for improving the outcomes in patients with CRAB bacteraemia.

6.
J Biophotonics ; : e202000321, 2020 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-32969170

RESUMO

Myelin is a key component of the peripheral nervous system, whose structure anomaly in the digital skin is implicated in neuropathy. Here we demonstrate an in vivo labeling and imaging technique, capable of visualizing myelin sheaths deep in the mouse digital skin. Through material characterization, we verify that 3-photon fluorescence (3PF) can be generated from a commonly used dye- FluoroMyelin Red for labeling myelin, excited at the 1700-nm window. Topical injection of FluoroMyelin Red in the mouse digit leads to bright labeling of myelin sheaths. Harnessing the deep-penetration capability of 3-photon microscopy excited at the 1700-nm window, we demonstrate that 3PF imaging of FluoroMyelin Red-labeled myelin sheaths in the mouse digit in vivo can be achieved to a depth 340 µm below the skin surface, revealing both branching bundle of and individual myelin sheaths.

7.
BMC Bioinformatics ; 21(Suppl 13): 386, 2020 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-32938388

RESUMO

BACKGROUND: In the field of computational biology, analyzing complex data helps to extract relevant biological information. Sample classification of gene expression data is one such popular bio-data analysis technique. However, the presence of a large number of irrelevant/redundant genes in expression data makes a sample classification algorithm working inefficiently. Feature selection is one such high-dimensionality reduction technique that helps to maximize the effectiveness of any sample classification algorithm. Recent advances in biotechnology have improved the biological data to include multi-modal or multiple views. Different 'omics' resources capture various equally important biological properties of entities. However, most of the existing feature selection methodologies are biased towards considering only one out of multiple biological resources. Consequently, some crucial aspects of available biological knowledge may get ignored, which could further improve feature selection efficiency. RESULTS: In this present work, we have proposed a Consensus Multi-View Multi-objective Clustering-based feature selection algorithm called CMVMC. Three controlled genomic and proteomic resources like gene expression, Gene Ontology (GO), and protein-protein interaction network (PPIN) are utilized to build two independent views. The concept of multi-objective consensus clustering has been applied within our proposed gene selection method to satisfy both incorporated views. Gene expression data sets of Multiple tissues and Yeast from two different organisms (Homo Sapiens and Saccharomyces cerevisiae, respectively) are chosen for experimental purposes. As the end-product of CMVMC, a reduced set of relevant and non-redundant genes are found for each chosen data set. These genes finally participate in an effective sample classification. CONCLUSIONS: The experimental study on chosen data sets shows that our proposed feature-selection method improves the sample classification accuracy and reduces the gene-space up to a significant level. In the case of Multiple Tissues data set, CMVMC reduces the number of genes (features) from 5565 to 41, with 92.73% of sample classification accuracy. For Yeast data set, the number of genes got reduced to 10 from 2884, with 95.84% sample classification accuracy. Two internal cluster validity indices - Silhouette and Davies-Bouldin (DB) and one external validity index Classification Accuracy (CA) are chosen for comparative study. Reported results are further validated through well-known biological significance test and visualization tool.


Assuntos
Algoritmos , Análise por Conglomerados , Biologia Computacional/métodos , Perfilação da Expressão Gênica/métodos , Proteômica/métodos , Humanos
8.
Zhongguo Gu Shang ; 33(8): 757-60, 2020 Aug 25.
Artigo em Chinês | MEDLINE | ID: mdl-32875768

RESUMO

OBJECTIVE: To analyze the clinical application value of adjustable skin retractor in large area of limb wound defect in children. METHODS: From January 2017 to January 2019, 11 children including 9 males and 2 females, aged 4 to 12 (8.3±2.7) years old with severe lower extremity wound defects were treated with adjustable skin stretch and closure device, all of them were unilateral lower extremity large area wound defects, including 4 cases of limb skin defect caused by traffic accident, 3 cases of failure to close after osteofasciotomy and decompression, 3 cases of plate exposure after internal fixation of lower extremity fracture and 1 case of ischemic necrosis after debridement and suturing of skin avulsion. The width of the wound was (5.6±1.2) cm and the length was (7.0±1.6) cm. VSD negative pressure drainage and expanded suture were used in all the patients. Four of them had been treated with free skin graft and two had been treated with local flap transfer. The graft or flap operation failed, and the effect of the early treatment was not good. RESULTS: After 5 to 14 (10.5±2.6) days of continuous traction, the wound was closed and no skin grafting or flap repair was performed. No complications such as poor blood supply, skin infection and necrosis, peripheral sensory disturbance occurred. All 11 patients were followed up for 3 to 18 (8.9±3.8) months. The wound edge skin was linear healing with slight scar. CONCLUSION: It is in accordance with Wolff's law and the concept of natural tissue reconstruction to treat large-scale limb wound defects in children with adjustable skin stretch and closure device, which provides an effective method for the treatment of limb skin and soft tissue defects in children.


Assuntos
Procedimentos Cirúrgicos Reconstrutivos , Lesões dos Tecidos Moles/cirurgia , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Transplante de Pele , Resultado do Tratamento , Cicatrização
9.
Chem Commun (Camb) ; 2020 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-32896849

RESUMO

A new approach in which a low symmetry cluster meets a low symmetry ligand to sharply boost the thermal stability of a MOF via additional inter-linker interactions is presented for the first time, leading to the successful synthesis of a novel binuclear Co-based MOF, {[Co2(L1)2DMF]·1.5DMF·0.75MeOH·1.5H2O}∞ (H2L1 = 5-(pyridin-3-yl) isophthalic acid, NJU-Bai62: NJU-Bai for Nanjing University Bai group), with exceptional thermal stability of up to 450 °C. This work may open up a new avenue for constructing robust MOFs from abundant, unstable, and low symmetry binuclear clusters, which have usually been ignored by most MOF chemists.

10.
iScience ; 23(9): 101472, 2020 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-32882513

RESUMO

ADAMTSs (a disintegrin and metalloproteinase with thrombospondin motifs) are secreted metalloproteinases that play a major role in the assembly and degradation of the extracellular matrix (ECM). In this study, we show that ADAMTS18, produced by the epithelial cells of distal airways and mesenchymal cells in lung apex at early embryonic stages, serves as a morphogen in lung development. ADAMTS18 deficiency leads to reduced number and length of bronchi, tipped lung apexes, and dilated alveoli. These developmental defects worsen lipopolysaccharide-induced acute lung injury and bleomycin-induced lung fibrosis in adult Adamts18-deficient mice. ADAMTS18 deficiency also causes increased levels of fibrillin1 and fibrillin2, bronchial microfibril accumulation, decreased focal adhesion kinase signaling, and disruption of F-actin organization. Our findings indicate that ECM homeostasis mediated by ADAMTS18 is pivotal in airway branching morphogenesis.

11.
Artigo em Inglês | MEDLINE | ID: mdl-32840957

RESUMO

Redox-active esters (RAEs) as active radical precursors have been extensively studied for C-B bond formations. However, the analogous transformations of stabilized radicals from the corresponding acid precursors remain challenging owing to the strong preference towards single-electron oxidation to the stable carbocations. This work describes a general strategy for rapid access to various aliphatic and aromatic boronic esters by mild photoinduced decarboxylative borylation. Both aryl and alkyl radicals could be generated from the leaving group-assisted N-hydroxybenzimidoyl chloride esters, even α-CF3 substituted substrates could be activated for further elaboration.

12.
Epidemiol Psychiatr Sci ; 29: e156, 2020 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-32792024

RESUMO

AIMS: Given the concerns of health inequality associated with mental illnesses, we aimed to reveal the extent of which general mortality and life expectancy at birth in people with schizophrenia, bipolar disorder and depressive disorder varied in the 2005 and 2010 nationally representative cohorts in Taiwan. METHODS: Two nationally representative samples of individuals with schizophrenia, bipolar disorder and depressive disorder were identified from Taiwan's national health insurance database in 2005 and 2010, respectively, and followed-up for consecutive 3 years. The database was linked to nationwide mortality registry to identify causes and date of death. Age-, gender- and cause-specific mortality rates were generated, with the average follow-up period of each age- and gender-band applied as 'weighting' for the calculation of expected number of deaths. Age- and gender-standardised mortality ratios (SMRs) were calculated for these 3-year observation periods with Taiwanese general population in 2011/2012 as the standard population. The SMR calculations were then stratified by natural/unnatural causes and major groups of death. Corresponding life expectancies at birth were also calculated by gender, diagnosis of mental disorders and year of cohorts for further elucidation. RESULTS: The general differential in mortality rates for people with schizophrenia and bipolar disorder remained wide, revealing an SMR of 3.65 (95% confidence interval (CI): 3.55-3.76) for cohort 2005 and 3.27 (3.18-3.36) for cohort 2010 in schizophrenia, and 2.65 (95% CI: 2.55-2.76) for cohort 2005 and 2.39 (2.31-2.48) for cohort 2010 in bipolar disorder, respectively. The SMRs in people with depression were 1.83 (95% CI: 1.81-1.86) for cohort 2005 and 1.59 (1.57-1.61) for cohort 2010. SMRs due to unnatural causes tended to decrease in people with major mental illnesses over the years, but those due to natural causes remained relatively stable. The life expectancies at birth for schizophrenia, bipolar disorder and depression were all significantly lower than the national norms, specifically showing 14.97-15.50 years of life lost for men and 15.15-15.48 years for women in people with schizophrenia. CONCLUSIONS: Compared to general population, the differential in mortality rates for people with major mental illnesses persisted substantial. The differential in mortality for unnatural causes of death seemed decreasing over the years, but that due to natural causes remained relatively steady. Regardless of gender, people with schizophrenia, bipolar disorder and depression were shown to have shortened life expectancies compared to general population.


Assuntos
Transtorno Bipolar/mortalidade , Transtorno Depressivo/mortalidade , Disparidades nos Níveis de Saúde , Esquizofrenia/mortalidade , Adulto , Idoso , Transtorno Bipolar/psicologia , Causas de Morte/tendências , Estudos de Coortes , Transtorno Depressivo/psicologia , Feminino , Humanos , Expectativa de Vida , Masculino , Pessoa de Meia-Idade , Mortalidade/tendências , Psicologia do Esquizofrênico , Fatores Socioeconômicos , Suicídio , Taiwan/epidemiologia
13.
Pathogens ; 9(8)2020 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-32823763

RESUMO

Prion disease is a group of transmissible neurodegenerative disorders affecting humans and animals. The prion hypothesis postulates that PrPSc, the pathogenic conformer of host-encoded prion protein (PrP), is the unconventional proteinaceous infectious agent called prion. Supporting this hypothesis, highly infectious prion has been generated in vitro with recombinant PrP plus defined non-protein cofactors and the synthetically generated prion (recPrPSc) is capable of causing prion disease in wild-type mice through intracerebral (i.c.) or intraperitoneal (i.p.) inoculation. Given that many of the naturally occurring prion diseases are acquired through oral route, demonstrating the capability of recPrPSc to cause prion disease via oral transmission is important, but has never been proven. Here we showed for the first time that oral ingestion of recPrPSc is sufficient to cause prion disease in wild-type mice, which was supported by the development of fatal neurodegeneration in exposed mice, biochemical and histopathological analyses of diseased brains, and second round transmission. Our results demonstrate the oral transmissibility of recPrPSc and provide the missing evidence to support that the in vitro generated recPrPSc recapitulates all the important properties of naturally occurring prions.

14.
Int J Mol Sci ; 21(15)2020 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-32825207

RESUMO

The author wishes to make the following correction to this paper [...].

15.
Life Sci ; 260: 118216, 2020 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-32768582

RESUMO

AIMS: Doxorubicin (DOX) is a potent anticancer drug with severe dose-dependent cardiotoxicity. To address this issue, previous research primarily focused on DOX-induced toxicity on cardiomyocytes. However, more recent research has looked into the endothelium as a therapeutic target due to the emerging role of endothelial cells in the support of cardiomyocyte survival and function. MAIN METHODS: We investigated a novel role of endothelial cell (EC) primary cilia in the prevention of DOX-mediated cardiotoxicity. Mice lacking EC primary cilia, via the deletion of EC-specific intraflagellar protein 88 (IFT88) expression, were administered DOX (20 mg/kg i.p.), and assessed for survival, cardiac function, cardiac structure changes, and indices of cardiomyocyte injury. KEY FINDINGS: DOX-treatment resulted in reduced survival and cardiac function (ejection fraction and fractional shortening) in EC-IFT88-/- mice vs. their similarly treated wild-type littermates. Cardiomyocyte vacuolization, cardiac fibrosis, and serum CK-MB levels were also increased in DOX-treated mice compared to saline-treated controls. However, these parameters were not significantly different when comparing WT and EC-IFT88-/- mice after DOX treatment. SIGNIFICANCE: The loss of EC primary cilia accelerated DOX-mediated mortality and reduced cardiac function, suggesting pathways downstream of ciliary-mediated signal transduction as potential targets to promote EC support of cardiomyocyte function during DOX treatment.

16.
Aging (Albany NY) ; 12(16): 16579-16596, 2020 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-32858529

RESUMO

Excessive light exposure is a principal environmental factor, which can cause damage to photoreceptors and retinal pigment epithelium (RPE) cells and may accelerate the progression of age-related macular degeneration (AMD). In this study, oxidative stress, endoplasmic reticulum (ER) stress and autophagy caused by light exposure were evaluated in vitro and in vivo. Light exposure caused severe photo-oxidative stress and ER stress in photoreceptors (661W cells) and RPE cells (ARPE-19 cells). Suppressing either oxidative stress or ER stress was protective against light damage in 661W and ARPE-19 cells and N-acetyl-L-cysteine treatment markedly inhibited the activation of ER stress caused by light exposure. Moreover, suppressing autophagy with 3-methyladenine significantly attenuated light-induced cell death. Additionally, inhibiting ER stress either by knocking down PERK signals or with GSK2606414 treatment remarkably suppressed prolonged autophagy and protected the cells against light injury. In vivo experiments verified neuroprotection via inhibiting ER stress-related autophagy in light-damaged retinas of mice. In conclusion, the above results suggest that light-induced photo-oxidative stress may trigger subsequent activation of ER stress and prolonged autophagy in photoreceptors and RPE cells. Suppressing ER stress may abrogate over-activated autophagy and protect the retina against light injury.

17.
Cells ; 9(8)2020 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-32756527

RESUMO

The property of drug-resistance may attenuate clinical therapy in cancer cells, such as chemoresistance to gefitinib in colon cancer cells. In previous studies, overexpression of PD-L1 causes proliferation and metastasis in cancer cells; therefore, the PD-L1 pathway allows tumor cells to exert an adaptive resistance mechanism in vivo. Nano-diamino-tetrac (NDAT) has been shown to enhance the anti-proliferative effect induced by first-line chemotherapy in various types of cancer, including colorectal cancer (CRC). In this work, we attempted to explore whether NDAT could enhance the anti-proliferative effect of gefitinib in CRC and clarified the mechanism of their interaction. The MTT assay was utilized to detect a reduction in cell proliferation in four primary culture tumor cells treated with gefitinib or NDAT. The gene expression of PD-L1 and other tumor growth-related molecules were quantified by quantitative polymerase chain reaction (qPCR). Furthermore, the identification of PI3K and PD-L1 in treated CRC cells were detected by western blotting analysis. PD-L1 presentation in HCT116 xenograft tumors was characterized by specialized immunohistochemistry (IHC) and the hematoxylin and eosin stain (H&E stain). The correlations between the change in PD-L1 expression and tumorigenic characteristics were also analyzed. (3) The PD-L1 was highly expressed in Colo_160224 rather than in the other three primary CRC cells and HCT-116 cells. Moreover, the PD-L1 expression was decreased by gefitinib (1 µM and 10 µM) in two cells (Colo_150624 and 160426), but 10 µM gefitinib stimulated PD-L1 expression in gefitinib-resistant primary CRC Colo_160224 cells. Inactivated PI3K reduced PD-L1 expression and proliferation in CRC Colo_160224 cells. Gefitinib didn't inhibit PD-L1 expression and PI3K activation in gefitinib-resistant Colo_160224 cells. However, NDAT inhibited PI3K activation as well as PD-L1 accumulation in gefitinib-resistant Colo_160224 cells. The combined treatment of NDAT and gefitinib inhibited pPI3K and PD-L1 expression and cell proliferation. Additionally, NDAT reduced PD-L1 accumulation and tumor growth in the HCT116 (K-RAS mutant) xenograft experiment. (4) Gefitinib might suppress PD-L1 expression but did not inhibit proliferation through PI3K in gefitinib-resistant primary CRC cells. However, NDAT not only down-regulated PD-L1 expression via blocking PI3K activation but also inhibited cell proliferation in gefitinib-resistant CRCs.

18.
Cephalalgia ; 40(12): 1321-1330, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32635765

RESUMO

OBJECTIVE: The current study explored whether the chances of having migraine are influenced by a youth's friendship with a migraineur. METHODS: The study was centered on a community-based non-referral cohort of eighth graders from two middle schools in Taiwan. Among the 642 recruited adolescent students, 610 (95%) (mean age 14.1 years, male ratio 51.2%) nominated three good friends and completed a validated headache questionnaire for migraine diagnosis at the follow-up survey 1 year later. To explore social influences on incident migraine, we used longitudinal statistical models to examine whether the development of migraine in one adolescent during the 1-year observational period was associated with that in his/her friends. RESULTS: Overall, 1700 social ties were established in the social network based on the reported lists of good friends. Randomization test for the homophily effect demonstrated that the students with migraine tended to cluster together in the social network even when those with incident migraine were also considered (p = 0.003). Besides, when friendship choices were mutual, the relative risk of an adolescent becoming a migraineur was 3.26 (95% CI: 1.25-8.47, p = 0.015) if his/her friend became a migraineur (induction) during the 1-year observational period. CONCLUSION: To the best of our knowledge, this is the first study to demonstrate that migraine may spread through social networks in young adolescents. Both homophily and induction effects are possibly contributory.

19.
Clin Transl Med ; : e129, 2020 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-32722861

RESUMO

Esophageal squamous cell carcinoma (ESCC) is more prevalent than esophageal adenocarcinoma in Asia, especially in China, where more than half of ESCC cases occur worldwide. Many studies have reported that the automatic detection of lymph node metastasis using semantic segmentation shows good performance in breast cancer and other adenocarcinomas. However, the detection of squamous cell carcinoma metastasis in hematoxylin-eosin (H&E)-stained slides has never been reported. We collected a training set of 110 esophageal lymph node slides with metastasis and 132 lymph node slides without metastasis. An iPad-based annotation system was used to draw the contours of the cancer metastasis region. A DeepLab v3 model was trained to achieve the best fit with the training data. The learned model could estimate the probability of metastasis. To evaluate the effectiveness of the detection model of learned metastasis, we used another large cohort of clinical H&E-stained esophageal lymph node slides containing 795 esophageal lymph nodes from 154 esophageal cancer patients. The basic authenticity label for each slide was confirmed by experienced pathologists. After filtering isolated noise in the prediction, we obtained an accuracy of 94%. Furthermore, we applied the learned model to throat and lung lymph node squamous cell carcinoma metastases and achieved the following promising results: an accuracy of 96.7% in throat cancer and an accuracy of 90% in lung cancer. In this work, we organized an annotated dataset of H&E-stained esophageal lymph node and trained a deep neural network to detect lymph node metastasis in H&E-stained slides of squamous cell carcinoma automatically. Moreover, it is possible to use this model to detect lymph nodes metastasis in squamous cell carcinoma from other organs. This study directly demonstrates the potential for determining the localization of squamous cell carcinoma metastases in lymph node and assisting in pathological diagnosis.

20.
EBioMedicine ; 58: 102894, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32707451

RESUMO

BACKGROUND: Daily oral pre- or post-exposure prophylaxis (PrEP or PEP) is highly effective in preventing HIV infection. However, many people find it challenging to adhere to a daily oral regimen. Chemoprophylaxis with single oral doses of antiretroviral drugs taken before or after sex may better adapt to changing or unanticipated sexual practices and be a desirable alternative to daily PrEP or PEP. We investigated willingness to use a single oral pill before or after sex among men who have sex with men (MSM) and assessed the biological efficacy of a potent antiretroviral combination containing elvitegravir (EVG), emtricitabine (FTC), and tenofovir alafenamide (TAF). METHODS: Data on willingness to use single-dose PrEP or PEP were obtained from the 2017 cycle of the American Men's Internet Survey (AMIS), an annual online behavioral surveillance survey of MSM in the United States. Antiretroviral drug levels were measured in humans and macaques to define drug distribution in rectal tissue and identify clinically relevant doses for macaque modeling studies. The biological efficacy of a single dose of FTC/TAF/EVG as PrEP or PEP was investigated using a repeat-challenge macaque model of rectal HIV infection. FINDINGS: Through pharmacokinetic assessment in humans and macaques we found that EVG penetrates and concentrates in rectal tissues supporting its addition to FTC/TAF to boost and extend chemoprophylactic activity. Efficacy estimates for a single oral dose given to macaques 4h before or 2h after SHIV exposure was 91•7%[35•7%-98•9%] and 100%, respectively, compared to 80•1%[13•9%-95•4%] and 64•6%[-19•4%-89•5%] when single doses were given 6 and 24h post challenge, respectively. A two-dose regimen at 24h and 48h after exposure was also protective [77•1%[1•7%-94•7%]. INTERPRETATION: Informed by user willingness, human and macaque pharmacokinetic data, and preclinical efficacy we show that single-dose prophylaxis before or after sex is a promising HIV prevention strategy. Carefully designed clinical trials are needed to determine if any of these strategies will be effective in humans. FUNDING: Funded by CDC intramural funds, CDC contract HCVJCG2-2016-03948 (to CFK), and a grant from the MAC AIDS Fund and by the National Institutes of Health [P30AI050409] - the Emory Center for AIDS Research (to MZ and TS).

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